Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs.
Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs.
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DOI：
10.1039/c3cs60459d
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发表时间：
2014-10-07
影响因子：
46.2
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Jang H;Arce FT;Ramachandran S;Kagan BL;Lal R;Nussinov R
无序的淀粉样蛋白生成肽聚集成寡聚体是淀粉样蛋白相关疾病的病原体。在溶液中，无序的蛋白质状态的特点是异质系综。其中，富含β的构象异构体通过构象选择机制自组装以形成能量有利的交叉β结构，而不管它们的精确序列如何。这些无序肽也可以穿透细胞膜，电生理数据表明它们形成离子传导通道。基于这些和额外的数据，包括一系列淀粉样肽的成像和分子动力学模拟，阿尔茨海默氏淀粉样蛋白-β（Aβ）肽，其疾病相关的点突变和N-末端截短的变体，其他淀粉样肽，以及细胞溶解肽和合成的凝胶形成肽，我们认为无序的淀粉样肽也可以在膜中呈现共同的基序。该基序由弯曲的、月亮状的富含β的寡聚体组成，这些寡聚体结合成环状组织。基序在脂质双层中是有利的，因为它允许疏水侧链面对膜并与膜相互作用，并且允许带电/极性残基面对溶剂化通道孔。这样的通道是有毒的，因为它们的孔允许离子不受控制地泄漏到细胞中/细胞外，使细胞离子稳态不稳定。在这里，我们详细介绍了Aβ，其聚集与阿尔茨海默病（AD）相关，并且有最丰富的数据。AD是一种蛋白质错误折叠疾病，其特征在于Aβ肽积聚为老年斑、神经变性和记忆丧失。兴奋性产生的Aβ肽可直接诱导细胞毒性，即使没有膜受体通过Aβ肽-质膜相互作用的参与。
Aggregation of disordered amyloidogenic peptides into oligomers is the causative agent of amyloid-related diseases. In solution, disordered protein states are characterized by heterogeneous ensembles. Among these, β-rich conformers self-assemble via a conformational selection mechanism to form energetically-favored cross-β structures, regardless of their precise sequences. These disordered peptides can also penetrate the membrane, and electrophysiological data indicate that they form ion-conducting channels. Based on these and additional data, including imaging and molecular dynamic simulations of a range of amyloid peptides, Alzheimer’s amyloid-β (Aβ) peptide, its disease-related variants with point mutations and N-terminal truncated species, other amyloidogenic peptides, as well as a cytolytic peptide and a synthetic gel-forming peptide, we suggest that disordered amyloidogenic peptides can also present a common motif in the membrane. The motif consists of curved, moon-like β-rich oligomers associated into annular organizations. The motif is favored in the lipid bilayer since it permits hydrophobic side chains to face and interact with the membrane and the charged/polar residues to face the solvated channel pores. Such channels are toxic since their pores allow uncontrolled leakage of ions into/out of the cell, destabilizing cellular ionic homeostasis. Here we detail Aβ, whose aggregation is associated with Alzheimer’s disease (AD) and for which there are the most abundant data. AD is a protein misfolding disease characterized by a build-up of Aβ peptide as senile plaques, neurodegeneration, and memory loss. Excessively produced Aβ peptides may directly induce cellular toxicity, even without the involvement of membrane receptors through Aβ peptide-plasma membrane interactions.
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影响因子：
3.3
作者：
Connelly, Laura;Jang, Hyunbum;Lal, Ratnesh
通讯作者：
Lal, Ratnesh
影响因子：
2.9
作者：
Chi, Eva Y.;Ege, Canay;Lee, Ka Yee C.
通讯作者：
Lee, Ka Yee C.
影响因子：
3.4
作者：
Arce FT;Jang H;Ramachandran S;Landon PB;Nussinov R;Lal R
通讯作者：
Lal R
影响因子：
4.2
作者：
Ciccotosto, Giuseppe D.;Tew, Deborah J.;Cappai, Roberto
通讯作者：
Cappai, Roberto
影响因子：
3.4
作者：
Chiu, Chi-cheng;Singh, Sadanand;de Pablo, Juan J.
通讯作者：
de Pablo, Juan J.